The latest trend that has, of late, crept into the pharmaceutical industry is the studies on polymorphism in drugs and the difference in the activity of different polymorphic forms of a given drug. By the term polymorphism we mean to include different physical forms, crystal forms, crystalline/liquid crystalline/non-crystalline (amorphous) forms. This has especially become very interesting after observing that many antibiotics, antibacterials, tranquilizers etc., exhibit polymorphism and some/one of the polymorphic forms of a given drug exhibit superior bio-availability and consequently show much higher activity compared to other polymorphs. Sertraline, Frentizole, Ranitidine, Sulfathiazole, Indomethacine etc. are some of the important examples of pharmaceuticals which exhibit polymorphism. Polymorphism in drugs is a topic of current interest and is evident from the host of patents being granted. To cite a few, U.S. Pat. No. 5,700,820 discloses six polymorphic forms of Troglitazone, U.S. Pat. No. 5,248,699 discusses about five polymorphic forms of Sertraline hydrochloride while EP 014590 describes four polymorphic forms of Frentizole. EP 490648 and EP 022527 also deal with the subject of polymorphism in drugs.
European Patent No. 0306338, International publication No. WO 94/25026 and U.S. patent application Ser. No. 5,646,169 describe that the relative configurations of the diastereomers have been determined by x-ray crystallographic analysis and that the crystal and molecular structure of the 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate is under preparation. The report does not touch upon the possibility/observation that 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]thoxy]enzyl]thiazolidine-2,4-dione maleate exists in different polymorphic forms. There is no published literature regarding such an observation till date. Polymorphism in drugs is a topic of current interest and is evident from the host of patents being granted to cite a few U.S. Pat. No. 5,248,699 discusses about five polymorphic forms of Sertraline hydrochloride while EP 014590, describes four polymorphic forms of Frentizole EP 490648 and EP 022527, six polymorphic forms of Troglitazone WO 97/27191 also deal with the subject of polymorphism in drugs. The fact that polymorphism in 5-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate has not been studied earlier coupled with the current interest in the field of polymorphism in drugs prompted us to take-up this investigation our observations and results from the subject matter of the present invention.
With a view to prevent/cure the chronic complications of diabetes, research is being conducted round the world in recent times. 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate is being considered today as one of the most effective anti-diabetic drugs which as a multi-purpose activity not only acting on diabetes itself but also on the reduction of the triglycerides and also on the accompanying complications mentioned above. Indeed the said 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate is emerging as the second drug candidate of euglycemic class of antidiabetic agents.
With an objective to develop novel polymorphic forms for lowering cholesterol and reducing body weight with beneficial effects in the treatment and/or prophylaxis of diseases related to increased levels of lipids, atherosclerosis, coronary artery diseases, Syndrome-X, impaired glucose tolerance, insulin resistance, insulin resistance leading to type 2 diabetes and diabetes complications thereof, for the treatment of diseases wherein insulin resistance is the pathophysiological mechanism and for the treatment of hypertension, with better efficacy, potency and lower toxicity, we focused our research to develop new polymorphic forms effective in the treatment of the above mentioned diseases. Effort in this direction has led to polymorphic forms having the formula (I).
Another objective of the present invention is to provide polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, their stereoisomers, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against PPARα and/or PPARγ, and optionally inhibit HMG CoA reductase, in addition to having agonist activity against PPARα and/or PPARγ.
Another objective of the present invention is to provide novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, their stereoisomers, pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, without toxic effect or with reduced toxic effect.
Yet another objective of the present invention to provide a process for the preparation of novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, their stereoisomers, pharmaceutically acceptable solvates.
Still another objective of the present invention is to provide pharmaceutical compositions containing novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.